Vascular disease, because of its effects upon the brain, heart, kidneys, extremities, and other vital organs, is a leading cause of morbidity and mortality in the United States and in most Western countries. In this regard, much has been learned about atherosclerosis, and the lipidemias, with particular reference to cholesterol. In particular, there is convincing evidence of a reciprocal relationship between a high serum cholesterol and the incidence of atherosclerosis and its complications. Much interest has been expressed in recent years in reducing the level of serum cholesterol. However, some studies have shown that even radical reductions in dietary cholesterol achieves a modest decrease of only 10 to 15% in plasma cholesterol. Thus, it has been appreciated that further reductions in serum cholesterol will require other therapeutic measures, including the inhibition of cholesterol synthesis in the body.
The enzymatic biosynthesis of cholesterol is a complex process which requires altogether some 25 reaction steps. The pathway can be divided into three stages: (1) the conversion of acetic acid to mevalonic acid; (2) the conversion of mevalonic acid into squalene; and, (3) the conversion of squalene into cholesterol. In the last stage of cholesterol biosynthesis, squalene is converted to squalene 2,3-epoxide via oxidation, a reaction catalyzed by squalene monooxygenase, also known as squalene epoxidase. The squalene 2,3-epoxide then undergoes cyclization to lanosterol, the first sterol to be formed; the cyclization of 2,3-oxidosqualene to lanosterol is catalyzed by the microsomal enzyme 2,3-oxidosqualene lanosterol-cyclase (squalene cyclase). Inhibition of either squalene epoxidase or squalene cyclase would result in the inhibition of cholesterol synthesis in animals. (See generally, Taylor, Frederick R., Kandutsch, Andrew A., Gayen, Apurba K., Nelson, James A., Nelson, Sharon S., Phirwa, Seloka, and Spencer, Thomas A., 24,25-Epoxysterol Metabolism in Cultured Mammalian Cells and Repression of 3-Hydorxy-3-methylglutaryl-CoA Reductase, The Journal of Biological Chemistry 261, 15039-15044 incorporated herein by reference.)
In addition, it has recently been reported that certain compounds, such as allylamines, act as inhibitors of squalene epoxidase and have potent antifungal activity. (See generally, Stutz, Anton, Allylamine Derivatives--A New Class of Active Substances in Antifungal Chemotherapy, Angew. Chem. Int. Ed. Engl., 26, 320-328 (1987)). Fungal infections (mycoses) are found throu9hout the world. Only a few structural classes of compounds currently satisfy the demands of modern chemotherapy in their treatment and the search for new types of active substances is of major therapeutic importance. As inhibitors of squalene epoxidase in animals, the compounds of the present invention are believed to be useful in the treatment of fungal infections through the inhibition of cholesterol biosynthesis.